MYC Overexpression Drives Immune Evasion in Hepatocellular Carcinoma That Is Reversible through Restoration of Proinflammatory Macrophages

Abstract

Cancers evade immune surveillance, which can be reversed through immune checkpoint therapy in a small subset of cases. Here we report that the MYC oncogene suppresses innate immune surveillance and drives resistance to immunotherapy. In 33 different human cancers, MYC genomic amplification and overexpression increased immune checkpoint expression, predicted non-responsiveness to immune checkpoint blockade, and was associated with both Th2-like immune profile and reduced CD8 T cell infiltration. MYC transcriptionally suppressed innate immunity and MHCI mediated antigen presentation, which in turn impeded T cell response. Combined, but not individual, blockade of PDL1 and CTLA4 could reverse MYC-driven immune suppression by leading to recruitment of pro-inflammatory antigen-presenting macrophages with increased CD40 and MHCII expression. Depletion of macrophages abrogated the anti-neoplastic effects of PDL1 and CTLA4 blockade in MYC-driven hepatocellular carcinoma (HCC). Hence, MYC is a predictor of immune checkpoint responsiveness and a key driver of immune evasion through the suppression of pro-inflammatory macrophages. The immune evasion by MYC in HCC can be overcome by combined PDL1 and CTLA4 blockade.

Liver cancer development driven by the AP-1/c-Jun~Fra-2 dimer through c-Myc (Author copy)

“…The cellular and molecular events occurring immediately after turning OFF c-Jun˜Fra-2, the involvement of Fos-containing dimers, and their connection to the various pro-tumorigenic functions of c-Myc certainly warrant further evaluation. Unbiased, possibly single-cell, RNA and proteome profiling of a large number of tumors in different ON and OFF settings and subsequent comparison with the OMIC data generated using c-Myc-switchable liver mice (55,56) will help narrowing down the essential molecular and cellular players.…”

Targeting MYC at the intersection between cancer metabolism and oncoimmunology

“…Moreover, a recent study by Dhanasekaran et al. ( 115 ), reported that MYC transcriptionally repressed MHC-1 antigen presentation and therefore repressed T-cell immune response in MYC-driven hepatocellular carcinoma. This phenomenon was pharmacologically reversible by the dual-inhibition of immune checkpoint molecules, PD-L1 and CTLA-4.…”

“…The approach of tackling MYC gene targets has also been successful in modulating the immune evasive nature of tumors. For instance, dual inhibition of MYC targets PD-L1 and CTLA-4 reverses MYC-driven immunosuppression through pro-inflammatory macrophages in hepatocellular carcinoma ( 115 ). Moreover, MYC partners with epigenetic modulators such as histone acetylases (HAT) and DNA methylases (DNMT), in the transcriptional activation of immunosuppressive gene targets of MYC ( 171 ).…”

“…Particularly in osteosarcoma, Jiang et al (114), observed that pharmacological inhibition of MYC resulted in reprogramming the tumor immune microenvironment through the release of T-cell recruiting chemokines and crosstalk of costimulatory immune checkpoint molecules CD40 and CD40L. Moreover, a recent study by Dhanasekaran et al (115), reported that MYC transcriptionally repressed MHC-1 antigen presentation and therefore repressed T-cell immune response in MYC-driven h e p a t o c e l l u l a r c a r c i n o m a . T h i s p h e n o m e n o n w a s pharmacologically reversible by the dual-inhibition of immune checkpoint molecules, PD-L1 and CTLA-4.…”

Association with TFIIIC limits MYCN localization in hubs of active promoters and chromatin accumulation of non-phosphorylated RNA Polymerase II

“…Both MYC and MYCN bind to virtually all active promotors and profoundly alter the dynamics of RNA polymerase II (RNAPII) transcription, with an increase in pause release and elongation being most apparent (Herold, Kalb et al, 2019, Walz, Lorenzin et al, 2014). One consequence of these changes are alterations in expression of a broad range of target genes (Dhanasekaran, Hansen et al, 2023). Unrelated to those changes in gene expression, MYC and MYCN also control RNAPII function to limit the accumulation of R-loops, to facilitate promoter-proximal double-strand break repair and to co-ordinate transcription elongation with DNA replication (Papadopoulos, Uhl et al, 2023).…”